Glucokinase (GK) (ATP: D-hexose 6-phosphotransferase, EC 2.7.1.1) is one (hexokinase IV) of four mammal hexokinases. Hexokinase is a first-stage enzyme in glycolysis and catalyzes a reaction from glucose to glucose hexaphosphate. In its expression, glucokinase is limited essentially in liver and pancreas beta cells, and it controls the rate-limiting step of glucose metabolism in these cells thereby playing an important role in systemic saccharometabolism. Glucokinase in liver and that in pancreas beta cells differ from each other in point of the N-terminal 15-amino acid sequence owing to the difference in splicing therebetween, but they are the same in point of the enzymatic property. The enzymatic activity of the other three hexokinases (I, II, III) than glucokinase is saturated at a glucose concentration of at most 1 mM, but Km of glucokinase to glucose is 8 mM and is near to a physiological blood-glucose level. Therefore, in accordance with the blood-glucose level change from a normal blood-glucose level (5 mM) to an increased blood-glucose level after meals (10 to 15 mM), intracellular glucose metabolism is accelerated via glucokinase.
Since ten years ago, a hypothesis that glucokinase may act as a glucose sensor in pancreas beta cells and liver has been proposed [for example, see Garfinkel D. et al's “Computer modeling identifies glucokinase as glucose sensor of pancreatic beta-cells”, American Journal Physiology, Vol. 247 (3Pt2), 1984, pp. 527-536]. A result of recent glucokinase gene-manipulated mice has clarified that glucokinase actually plays an important role in systemic glucose homeostasis. Mice in which the glucokinase gene was disrupted die soon after their birth [for example, see Grupe A. et al's “Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis”, Cell, Vol. 83, 1995, pp. 69-78]; but on the other hand, normal or diabetic mice in which glucokinase was excessively expressed have a lowered blood-glucose level [for example, see Ferre T. et al's “Correction of diabetic alterations by glucokinase”, Proceedings of the National Academy of Sciences of the U.S.A., Vo. 93, 1996, pp. 7225-7230]. With the increase in glucose concentration therein, the reaction of pancreas beta cells and that of liver cells are both toward the reduction in a blood-glucose level, though differing from each other. Pancreas beta cells come to secrete more insulin, and liver takes up sugar to store it as glycogen therein and simultaneously reduces sugar release.
To that effect, the change in the enzymatic activity of glucokinase plays an important role in mammal glucose homeostasis via liver and pancreas beta cells. In a juvenile diabetic case that is referred to as MODY2 (maturity-onset diabetes of the young), mutation of a glucokinase gene has been found, and the glucokinase activity reduction causes the blood-glucose level increase [for example, see Vionnet N. et al's “Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus”, Nature Genetics, Vol. 356, 1992, pp. 721-722]. On the other hand, a pedigree having mutation of increasing glucokinase activity has been found, and those of the family line show low blood-glucose level symptoms [for example, see Glaser B. et al's “Familial hyperinsulinism caused by an activating glucokinase mutation”, New England Journal Medicine, Vol. 338, 1998, pp. 226-230].
From these, glucokinase acts as a glucose sensor and plays an important role in glucose homeostasis also in humans. On the other hand, blood-glucose level control by utilizing a glucokinase sensor system may be possible in many type-II diabetes patients. A glucokinase-activating substance may be expected to have an insulin secretion promoting effect in pancreas beta cells and have a sugar take-up accelerating and sugar release inhibiting activity in liver, and therefore it may be useful as a remedy for type-II diabetes patients.
Recently, it has become clarified that pancreas beta cell-type glucokinase is limitedly expressed locally in rat brains, especially in ventromedial hypothalamus (VMH) thereof. About 20% neurocytes in VMH are referred to as glucose-responsive neurons, and heretofore it has been considered they may play an important role in body weight control. When glucose is administered to a rat brain, then it reduces the amount of ingestion; but when glucose metabolism is retarded through intracerebral administration of glucosamine, a glucose analogue, then it causes hyperphagia. From an electrophysiological experiment, it is admitted that glucose-responsive neurons are activated in accordance with a physiological glucose concentration change (5 to 20 mM), but when glucose metabolisms is inhibited by glucosamine or the like, then their activity is retarded. In the glucose concentration-sensitive system in VMH, a glucose-mediated mechanism is anticipated like the insulin secretion in pancreas beta cells. Accordingly, there may be a possibility that a substance for glucokinase activation in VMH, in addition to liver and pancreas beta cells, may be effective not only for blood-glucose level correction but also for solution of obesity that is problematic in many type-II diabetes patients.
From the above description, a compound having a glucokinase activation effect is useful for remedies and/or preventives for diabetes, or for remedies and/or preventives for chronic complications of diabetes such as retinopathy, nephropathy, neurosis, ischemic cardiopathy, arteriosclerosis, and further for remedies and/or preventives for obesity.
As a compound structurally similar to the indole derivative (I) of the invention, for example, a compound represented by the following formula (A):
is disclosed (for example, see WO2002/032872).
The compound of the above formula (A) differs from the compound of the invention in that in the former, the amino group of the pyrrole ring of the pyrrolo[2,3-d]pyrimidine skeleton is protected with a methyl group, but in the latter, it is not protected. In addition, the two further differ in that, in the compound of the above formula (A), two aliphatic heterocyclic groups bond to the pyrrolo[2,3-d]pyrimidine skeleton, but the compound of the invention does not include those in which two aliphatic heterocyclic groups bond to the indole skeleton.
Moreover, the diseases to which the above formula (A) is directed are subarachnoid hemorrhage and ischemic stroke after it, etc.; and they differ from the diseases to which the compound of the invention is directed.